This invention relates to derivatives of polyene macrolide antibiotics and more particularly is directed to the provision of new compounds of this class, having significant advantages or characteristics while exhibiting the antimicrobial or biological activity of the underlying or base substances.
The polyene macrolide antibiotics are a well recognized class of compounds, conventionally produced by cultivation of various suitable organisms and by extraction of the substance from the culture. They are primarily recognized as antifungal agents, although in one instance or another they may exhibit significantly useful activity against other micro-organisms. The compounds are basically and uniquely characterized by a large lactone ring which includes a chain of conjugated double bonds, specifically comprising 4, 5, 6 and 7 such linkages, whereby the compounds are correspondingly known as tetraenes, pentaenes, hexaenes and heptaenes and are collectively called polyenes. Thus the base antibiotics are high molecular weight (e.g. in the range of 700-1200) macrocyclic lactones, known as macrolides, and since they contain an amino sugar moiety, can be described as comprising an amino sugar glycoside of a macrolide nucleus that possesses a chromophore of 4 to 7 conjugated double bonds.
As a class, the molecular structure of the base compounds has been quite well defined, in that in all cases it primarily consists of a macrocyclic lactone nucleus which is a long chain of carbon atoms (e.g. in the range of 20 to 40) closed by a single lactone oxygen atom to constitute the macrolide ring and having a carbonyl oxygen on a carbon atom of the ring immediately adjacent to the lactone oxygen, as is characteristic of lactones. The carbon atoms are directly, successively linked to each other along the ring by single or double bonds, mostly single bonds, but in all cases with the important situation of the uninterrupted series of conjugated double bonds specified above. As stated, the compound also includes a single amino sugar, linked to the ring as a substituent and carrying a free primary amine group. There are also a plurality of --OH groups which are attached respectively to a plurality of carbon atoms of the ring (other than the double-bonded atoms) and finally, in those of the polyene macrolides to which the present invention is directed, there is a single carboxyl group, also linked to the ring as a substituent. Additional substitution is normally found, which varies among specific members of the class, but is not deemed to alter the basically unique molecular structure or indeed the fundamental characteristics of these compounds as antifungal agents. The additional substitution involves substituents of one or more types such as various alkyls, oxygen, epoxy, and in a number of cases, groups that may be designated as aryl amine moieties.
The compositions are further defined hereinbelow, including a number of specifically elucidated examples, but it will be understood that the base polyene antifungal antibiotics constitute a recognized class of substances, being macrolides critically distinguished by the above defined composition, including particularly the stated chain of conjugated double bonds, and thus specifically distinguished from other chemical compounds, including other macrocyclic lactones.
As will be apparent, the members of the class to which the present invention is directed, being characterized by a free carboxyl group, have been recognized as amphoteric, by reason of the presence of such group and also the free amino radical in the amino sugar. Indeed the amphoteric nature of these water-insoluble compounds has contributed, as will be apparent below, to past difficulty in trying to convert them to water-soluble form.
Examples of this specific class of amphoteric antifungal antibiotics include: amphotericin A, nystatin, pimaricin and rimocidin, all tetraenes; eurocidin, a pentaene; cryptocidin and mediocidin, hexaenes; and amphotericin B, candicidin, candidin, candimycin, hamycin, levorin and trichomycin, which are heptaenes.
Although the antibiotics of this class have been recognized as significantly active, chiefly against fungus organisms, and a number of such antibiotics have been extensively used and are commercially available, they have been generally limited in utility by lack of effective water solubility or equivalent dispersibility in water. In some instances so-called salts, such as sodium salts, have been produced by reaction of alkali with the carboxyl group, to yield a substance having some water solubility, but such products have only exhibited solubility at a relatively high pH and have suffered from deterioration of their stability. On the other hand, efforts to produce so-called acid salts by acid addition to the amino group have been either ineffectual or of little or no utility in that the water soluble properties are then only exhibited at undesirably low pH values and with considerable instability.
In U.S. Pat. No. 3,244,590, a class of N-acyl derivatives of the heptaene antibiotics is disclosed, which retain some anti-microbial activity and which are convertible into water soluble salts (by alkaline reaction with a carbonyl group) yielding some utility in water. If has been found, however, that in at least a number of cases, the biological activity is substantially reduced and thus while these water soluble, N-acyl derivatives have some utility, there has remained a considerable need for products useful with substantially high activity in aqueous media.
Another procedure for achieving a water dispersible composition has been exemplified by the preparation of a complex of amphotericin B with desoxycholic acid, which acts as a detergent. Complexes of this type, however, do not form true solutions; the substance appears merely to be dispersed as a colloid, and the field of utility is correspondingly limited.
In a more general sense the invention is concerned with improvement of the polyene antibiotics not only with respect to attainment of substantial water solubility, but also in relation to other possibilities of use. For example, although the base compounds are soluble in a number of organic solvents, difficulty is encountered in some circumstances of potential value, as for example where it may be desirable to carry the antibiotic in a lipid base, i.e., such as an ointment or cream having a significant fat content and desired to be substantially non-aqueous. In all of these respects, but most especially in regard to the provision of water soluble products, an important aim of the present invention, among other objects as will be apparent, is to provide new and unusually valuable derivatives of these antibiotics.